Dopamine (DA) is a neurotransmitter that is important in locomotor control, reward circuitry, cognitive function, prolactin release and a variety of other key physiological functions. Dopaminergic dysfunctions have been implicated in Parkinson's disease, schizophrenia, addiction, attention deficit hyperactivity disorder (ADHD), and certain sexual dysfunctions.
It is has been reported that there are at least two pharmacological subtypes of dopamine receptors (the D1 and D2 receptor subtypes), each consisting of several molecular forms. D1 receptors preferentially recognize the phenyltetrahydrobenzazepines and generally lead to stimulation of the enzyme adenylate cyclase, whereas D2 receptors recognize the butyrophenones and benzamides and often are coupled negatively to adenylate cyclase, or are not coupled at all to this enzyme. It has also been reported that at least five dopamine receptor genes encode the D1, D2, D3, D4 and D5 receptor isoforms or subtypes. The traditional classification of dopamine receptor subtypes, however, remains useful with the D1-like class comprising the D1 (D1A) and the D5 (D1B) receptor subtypes, whereas the D2-like class consists of the D2, D3 and D4 receptor subtypes. Agonist stimulation of dopamine D1 receptors is believed to activate adenylate cyclase to form cyclic AMP (cAMP), which in turn is followed by the phosphorylation of intracellular proteins. Agonist stimulation of D2 dopamine receptors is believed to lead to decreased cAMP formation. Agonists at both subclasses of receptors are clinically useful. In addition, antagonists at both subclasses of receptors are clinically useful.
Dopamine receptor agonists are of therapeutic interest for a variety of reasons. For example, it has been hypothesized that excessive stimulation of D2 dopamine receptor subtypes may be linked to schizophrenia. Additionally, it is generally recognized that either excessive or insufficient dopaminergic activity in the central nervous system can cause hypertension, narcolepsy, and other behavioral, neurological, physiological, and movement disorders, including Parkinson's disease. For example, schizophrenia is among the most common and the most debilitating of psychiatric diseases. Current estimates suggest a prevalence of schizophrenia at between 0.5 and 1% of the population.
Patients with schizophrenia and other neurological and psychiatric disorders, such as psychosis, bipolar disorder, anxiety states, and depression in combination with psychotic episodes, can have both “positive” symptoms, including delusions, hallucinations, impaired cognitive function, and agitation, as well as “negative” symptoms, including emotional unresponsiveness, impaired memory, and impaired cognitive function. Patients with these psychotic signs and symptoms can be treated with drugs that fall into the general classes of typical antipsychotic drugs and atypical antipsychotic drugs. The typical antipsychotic agents include phenothiazines, butyrophenones, and other non-phenothiazines such as loxapine and molindone. The atypical antipsychotic agents include the clozapine-like drugs, such as clozapine, olanzepine, quetiapine, ziprasidone, and the like, as well as several others, including risperidone, aripiprazole, and amisulpiride, among others. Whereas both of these typical and atypical antipsychotic agents are useful for treating the positive symptoms of the neurological disorders described herein, patients may not find total relief from the negative symptoms that may accompany these antipsychotic agents. In addition, recent studies suggest that the current antipsychotic therapy for treating positive symptoms of schizophrenia may in some cases exacerbate or facilitate the onset of such negative symptoms.
Dopamine agonists have also been developed to treat Parkinson's disease in an attempt to avoid some of the limitations of levodopa therapy, because levodopa therapy is not always a successful treatment, for example in certain late-stage disorders. In addition, by acting directly on postsynaptic dopamine receptors, selective dopamine agonists bypass the degenerating presynaptic neurons. Furthermore, these drugs do not rely on the same enzymatic conversion for activity required for levodopa, avoiding issues associated with declining levels of striatal dopa decarboxylase. In addition, agonists have the potential for longer half-lives than levodopa, and can also be designed to interact specifically with predetermined subpopulations of dopamine receptors.
However, it has been shown that administering a D2 receptor antagonist down regulates D1 receptors. Such down regulation was shown to have the overall effect of causing or increasing memory and cognition complications. Down regulation of D1 and/or D5 receptor mRNAs has been observed in the prefrontal and temporal cortices but not in the neostriatum of nonhuman primates after chronic treatment with certain antipsychotic medications.
In addition, numerous reports have been made that full D1 agonists may cause D1 receptor desensitization and even down regulation of dopamine D1 receptor expression. Partial D1 agonists may cause desensitization but generally do not cause down regulation of receptor expression. In addition, it has also been shown that short-term administration of a D1 receptor agonist following the onset of memory or cognition complications arising from administering a D2 receptor antagonist, alleviated the symptoms of such memory or cognition complications.
Accordingly, a need still exists for additional agonists and antagonists of dopamine receptors. In addition, full agonists at dopamine receptors are also needed. In addition, agonists and antagonists that show dopamine receptor subtype selectivity are also needed.
It has been discovered that compounds described herein are modulators of dopamine receptors, including agonists and antagonists of dopamine receptors. In addition, compounds described herein are full agonists at dopamine receptors. In addition, compounds described herein are agonists and antagonists that show dopamine receptor subtype selectivity are also needed. In one embodiment, compounds are described herein that are agonists selective for D1 and/or D1-like dopamine receptors
In another embodiment, octahydrobenzo[h]isoquinoline compounds are described herein, such as compounds of the following formula
including pharmaceutically acceptable salts thereof, wherein:
RA is hydrogen; or RA represents 1-4 substituents selected from the group consisting of halo, hydroxy, and amino, and derivatives thereof, and alkyl and heteroalkyl, each of which is optionally substituted; where two adjacent substituents are optionally taken together with the attached carbons to form an optionally substituted heterocycle;
RB is hydrogen; or RB is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and
RN is hydrogen or an amino prodrug group; or RN is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.
In another embodiment, compositions are described herein for treating neurological, psychotic, and/or psychiatric disorders. The compositions include therapeutic amounts of one or more compounds described herein, which may be administered to a patient or subject in need of relief from or suffering from the neurological, psychotic, and/or psychiatric disorder. The compositions described herein may include pharmaceutically active carriers, diluents, and/or excipients.
In another embodiment, methods are described herein for treating neurological, psychotic, and/or psychiatric disorders. The methods include the step of administering therapeutic amounts of one or more compounds described herein to a patient or subject in need of relief from or suffering from the neurological, psychotic, and/or psychiatric disorder.
In another embodiment, uses are described herein for manufacturing medicaments for treating neurological, psychotic, and/or psychiatric disorders. The medicaments include therapeutic amounts of one or more compounds described herein, which may be used to treat to a patient or subject in need of relief from or suffering from the neurological, psychotic, and/or psychiatric disorder.